FDG

10.1.1 Radiopharmaceutical:

• [¹⁸F]Fluoro-2-deoxy-2-d-glucose, also known as:
  • [¹⁸F]Fluorodeoxyglucose
  • [¹⁸F]FDG

10.1.2 Uptake mechanism /biology of the tracer

[¹⁸F]FDG is a glucose analogue which accumulates in tissue in proportion to the amount of glucose utilization. Increased consumption of glucose is characteristic of most cancers and is mostly related to overexpression of the GLUT glucose transporters and increased hexokinase activity. Once inside the cell, FDG is phosphorylated by the enzyme hexokinase and trapped.

10.1.3 Indications

[¹⁸F]FDG PET/CT has become one of the cornerstones of patient management in oncology.

Indications for [¹⁸F]FDG PET/CT include, but are not limited to, the following:

• Differentiation between benign and malignant lesions;
• Screening for an unknown primary tumour when metastatic disease is discovered as the first manifestation of cancer or when the patient presents with a para-neoplastic syndrome;
• Initial staging patients with known malignancies;
• Monitoring response to therapies on known malignancies;
• Distinguishing residual active tumour from post-treatment fibrosis or necrosis;
• Detecting tumour recurrence (restaging), especially in the presence of elevated tumour markers;
• Selection of a metabolically active region within a tumour most likely to yield diagnostic information for biopsy;
• Guiding radiation therapy planning

10.1.4 Contra-indications

Pregnancy is a relative contra-indication.

It is not recommended to interrupt breast feeding [3].

10.1.5 Clinical performances

The medical literature dealing with the many and diverse indications of [¹⁸F]FDG PET/CT is too abundant to be summarized here, and the reader is referred to the EANM procedure guidelines for tumour imaging and the UK Royal College of Radiologists evidence-based use of PET/CT [61,178].

10.1.6 Activities to administer

The suggested activities to administer depend on patient weight, acquisition time per bed position and bed overlap, for a PET bed overlap <30%, the EANM guideline advices the minimum activity [¹⁸F]FDG to be:

• [¹⁸F]FDG (MBq) = 14 (MBq.min.bed^-1.kg^-1) Patient weight (kg) / Time per bed position (min.bed-1)
• e.g. for a 75 kg patient with 3 min acquisition time per bed position 350 MBq.

In paediatric nuclear medicine, the activities should be modified according to the EANM paediatric dosage card (https://www.eanm.org/publications/dosage-calculator/). The minimum recommended activity to administer is 26 MBq.

10.1.7 Dosimetry

The effective dose for [¹⁸F]FDG is 19 µSv/MBq [3]. The organ with the highest absorbed dose is the urinary bladder wall: 130 µGy/MBq

The range in effective dose for [¹⁸F]FDG is: 3.5-10 mSv per procedure.

The radiation exposure related to a CT scan carried out as part of an [¹⁸F]FDG PET/CT study depends on the intended use of the CT study and may differ from patient to patient.

Caveat: “Effective Dose” is a protection quantity that provides a dose value related to the probability of health detriment to an adult reference person due to stochastic effects from exposure to low doses of ionizing radiation. It should not be used to quantify the radiation risk for a single individual associated with a particular nuclear medicine examination. It is used to characterize a certain examination in comparison to alternatives, but  it should be emphasized that if the actual risk to a certain patient population is to be assessed, it is mandatory to apply risk factors (per mSv) that are appropriate for the gender, the age distribution and the disease state of that population."

10.1.8 Interpretation criteria / major pitfalls

[¹⁸F]FDG PET images should be displayed with and without attenuation correction. On all slices (of the attenuation corrected data), quantitative information with respect to size and [¹⁸F]FDG uptake can be retrieved. Images must be evaluated using software that is able to display fused PET and CT data and use an SUV scale.

The presence or absence of abnormal [¹⁸F]FDG accumulation on the PET images, especially focal accumulation, in combination with intensity of uptake and anatomical size should be evaluated. Absence of tracer accumulation in anatomical abnormalities seen on the CT scan or other imaging may be equally significant. When appropriate, the report should correlate PET/CT findings with those of other diagnostic tests, interpret them in that context and consider them in relation to the clinical data. For response assessment, the images should be viewed over the same dynamic grey scale or colour scale range, i.e., a fixed colour scale; for example, from SUV = 0 to SUV = 10 using an inverse linear scale. Both uncorrected and attenuation-corrected images may need to be reviewed to identify artefacts caused by contrast agents, metal implants and/or patient motion. In clinical trials, criteria for visual analysis should be defined a priori within the study protocol. SUV is increasingly used in clinical studies in addition to visual assessments. SUV is a measurement of the uptake in a tumour normalized on the basis of a distribution volume. Most of the published literature relates to SUV (normalized to body weight) measurements. SUV normalized to lean body mass (LBM) is referred to as SUL and is a recommended quantitative measure of [¹⁸F]FDG uptake. SUL should preferably be calculated alongside SUV.

Physiological [¹⁸F]FDG distribution and interpretation criteria:

• Accumulation of [¹⁸F]FDG can normally be seen in the brain, heart, kidneys, and urinary tract at 60 min after injection. The brain has a high uptake of [¹⁸F]FDG (about 7 % of injected activity). The myocardium in a typical fasting state primarily uses free fatty acids, but after glucose load it uses glucose. In the fasting state, FDG uptake in the myocardium should be low, but this is variable. Unlike glucose, [¹⁸F]FDG is excreted by the kidneys into the urine and accumulates in the urinary tract. There is some degree of [¹⁸F]FDG accumulation in muscles that can be increased by serum insulin or following exercise. Uptake in the gastrointestinal tract varies from patient to patient and may be increased, for example, in patients taking metformin. Uptake is common in lymphoid tissue in Waldeyer’s ring and in the lymphoid tissue of the terminal ileum and caecum. Physiological thymic uptake may be present, especially in children and young adults. Uptake in brown adipose tissue may be observed more commonly in young patients, and when the ambient temperature is low. No physiological uptake is noted in bone itself (unless free ¹⁸F-fluoride is present as a contaminant), but bone marrow uptake can be present to a variable degree in patients receiving growth factors (granulocyte colony-stimulating factor and granulocyte macrophage) as well as in patients with marrow proliferation for other reasons such as infection, inflammation or anaemia, and following chemotherapy.
• Due to the high physiological [¹⁸F]FDG uptake in the brain, [¹⁸F]FDG PET/CT is of limited value for detection of brain metastases. Consequently, [¹⁸F]FDG PET/CT is generally not used for the primary detection or exclusion of brain metastases.
• Increased [¹⁸F]FDG uptake is observed in many neoplastic lesions, granulation tissue (e.g. wound healing), infections and other inflammatory processes. A detailed description of pitfalls and situations that can lead to false-positive (benign processes that can show [¹⁸F]FDG uptake) or false negative [¹⁸F]FDG PET/CT interpretation has been published.
• Patterns of [¹⁸F]FDG uptake, established CT morphological criteria and correlation with patient history, physical examination and other imaging modalities may be helpful for differentiation between malignant lesions and benign uptake.
• SUVs and related quantitative measures, such as metabolic tumour volume and total lesion glycolysis have gained increasing importance for therapy response monitoring and for prognostic assessment.
• There is no single lower limit of the intensity of [¹⁸F]FDG uptake for the detection of abnormal uptake within lesions as it depends on the degree of contrast between the tumour and its immediate surroundings. This contrast is related to several pathophysiological factors, the most significant of which are histology ([¹⁸F]FDG avidity of the type of tumour), volume of vital tumour cells, movement during static acquisition (e.g. blurred signals in the case of pulmonary foci) and physiologically high uptake in adjacent background. Furthermore, the sensitivity of [¹⁸F]FDG PET/CT may be reduced in diabetic patients with elevated glucose levels.
• Although there are no conclusive data on the optimum interval between chemotherapy and [¹⁸F]FDG PET/CT, an interval of at least 10 days and preferably 3 weeks between the last treatment and the [¹⁸F]FDG PET/CT is generally considered adequate for measurement of response. This is because of the balance between any possible effects on tumour metabolism (such as macrophage impairment) and systemic effects (such as bone marrow activation following bone marrow depression, which may or may not be caused by growth factors). If an interval of 10 days is not possible, [¹⁸F]FDG PET/CT should be delayed as long as possible after the previous chemotherapy administration (i.e., until as close as possible to the next treatment cycle).
• The effects of growth factors (granulocyte colony-stimulating factor and granulocyte macrophage) on [¹⁸F]FDG biodistribution (due to enhanced bone marrow uptake) generally last for more than 2 weeks after the final administration.
• It is assumed that the (side) effects of radiotherapy are longer-lasting; investigation of patients with head and neck carcinoma treated with radiation has shown that radiation-induced inflammation can be seen on the [¹⁸F]FDG PET/CT images for 2-3 months after the end of treatment.
• In patients who have undergone surgery, uptake depends on the extent of surgery, the presence of infection/inflammation in the wound, and how long after surgery images are acquired. For example, there are few visible signs of a mediastinoscopy after 10 days, but sternotomy signs will remain visible for months. Following surgery, it is recommended that the [¹⁸F]FDG PET/CT be delayed for at least 6 weeks due to postsurgical inflammation, if the scan is primarily being done to assess the surgical field.
• [¹⁸F]FDG PET/CT for diagnostic purposes is generally assessed using visual criteria, looking for focally increased uptake that may represent malignancy in the appropriate clinical context. It is unclear how SUV can contribute to patient assessment, partly because of the considerable variability in the methodology used.

10.1.9 Patient preparation

The main purpose of patient preparation is to reduce tracer uptake in normal tissue (kidneys, bladder, skeletal muscle, myocardium, brown fat) while maintaining and optimizing tracer uptake in the target structures (tumour tissue) and keeping patient radiation exposure levels as low as reasonably possible.

Instructions to patients

Non-diabetic patients should not consume any food or liquids other than plain (unflavoured) water for at least 4 h prior to the start of the [¹⁸F]FDG PET/CT study (i.e., with respect to the time of injection of [¹⁸F]FDG). In practice, this means that patients scheduled to undergo the [¹⁸F]FDG PET/CT study in the morning should not eat after midnight and preferably should have only a light meal (no alcohol and only a small amount of carbohydrates) during the evening prior to the [¹⁸F]FDG PET/CT study. Those scheduled for an afternoon [¹⁸F]FDG PET/CT study may have a light breakfast at least 4 h prior to the time of their PET/CT appointment.

Medication can be taken as prescribed.

Adequate pre-hydration is important to ensure a sufficiently low concentration of [¹⁸F]FDG in the urine (fewer artefacts) and for radiation safety reasons. For example, consumption of 1 liter of water during the 2 h prior to injection is suggested. Where necessary, account for the volume of water in oral contrast agent if it is to be given for a diagnostic CT scan.

Coffee or caffeinated beverages are not recommended because even if “sugarless”, they may contain traces of simple carbohydrates and have the potential to induce excitant effects; this may also be the case for “sugar-free” beverages.

Parenteral nutrition and intravenous fluids containing glucose should be discontinued at least 4 h before the time of [¹⁸F]FDG injection. In addition, the infusion used to administer intravenous pre-hydration must not contain glucose.

During the injection of [¹⁸F]FDG and the subsequent uptake phase, the patient should remain seated or recumbent and silent (this is particularly true for head and neck cancer patients) to minimize [¹⁸F]FDG uptake in muscles.

The patient should be kept warm starting 30-60 min before the injection of [¹⁸F]FDG and continuing throughout the subsequent uptake period and examination to minimize [¹⁸F]FDG accumulation in brown fat (especially relevant in winter or if the room is air- conditioned).

Patients must avoid strenuous exercise for at least 6 h before the [¹⁸F]FDG PET/CT study, and preferably for 24 h.

Patients should void their bladder immediately prior to the PET/CT to reduce urinary bladder activity.

The patient should be able to lie still in the PET/CT system for the duration of the examination (10-20 min). A specific inquiry about claustrophobia at the time the patient is scheduled for the study may decrease the number of non-diagnostic studies, cancellations, and allow premedication planning.

If possible, the patient should put his/her arms above the head; proper supporting devices (e.g. foam pallets) provided by the manufacturers should be employed whenever feasible.

When a diagnostic contrast-enhanced CT examination with intravenous contrast agent is to be performed, specific indications must be followed.

Blood glucose

If the plasma glucose level is lower than 11 mmol/L (about 200 mg/dL), the [¹⁸F]FDG PET/ CT study can be performed.

If the plasma glucose level is higher than or equal to 11 mmol/L (about 200 mg/dL, the [¹⁸F]FDG PET/CT study should be rescheduled or the patient excluded depending on the patient’s circumstances.

Diabetes

The following recommendations apply to patients with diabetes mellitus:

• Type II diabetes mellitus (controlled by oral medication):
  • The [¹⁸F]FDG PET/CT study should be performed in the late morning.
  • Patients must comply with the fasting rules indicated above.
  • Patients continue to take oral medication to control their blood sugar. If intravenous contrast agent is going to be administered, metformin should be discontinued at the time of the examination and withheld for 48 h after the examination (see below).
• Type I diabetes mellitus and insulin-dependent type II diabetes mellitus
  • Ideally, an attempt should be made to achieve normal glycaemic values prior to the [¹⁸F]FDG PET/CT study, in consultation with the patient and his/her attending medical doctor.
  • There are three options for scheduling the [¹⁸F]FDG PET/CT study:
• It can be scheduled for the late morning or midday. The patient should eat a normal breakfast by early morning (around 7:00 a.m.) and inject the normal amount of insulin. Thereafter the patient should not consume any more food or fluids, apart from the prescribed amount of water. [¹⁸F]FDG should be injected no sooner than 4 h after subcutaneous injection of rapid-acting insulin or 6 h after subcutaneous injection of short-acting insulin. [¹⁸F]FDG administration is not recommended on the same day as the injection of intermediate-acting and/or long-acting insulin.
• It can be scheduled for the early morning. The presence of intermediate-acting insulin administered the evening before should not interfere with the PET/CT study and glycaemia will probably still be under control. If long-acting insulin was used the evening before, there could be a slight interference with the PET/CT study. Thus, if this is the preferred schedule, intermediate-acting (instead of long-acting) insulin is recommended. The patient should eat a normal breakfast after the PET/CT study and inject the normal amount of insulin.

In patients on continuous insulin infusion, if possible the [¹⁸F]FDGPET/CT study should be scheduled for the early morning. The insulin pump should be switched off for at least 4 h prior to [¹⁸F]FDG administration. The patient can have breakfast after the [¹⁸F]FDG PET/CT study and switch on continuous insulin infusion

10.1.10 Methods

The detailed recommendations are available in the FDG PET/CT:EANM procedure guidelines for tumour imaging: version 2.0  [61].